Allylic Alkylation Reaction

Allylic alkylation is probably the only reaction that could dispute the honorific title of benchmark test for new chiral NHCs to conjugate addition. In fact, most chiral NFICs are tested in both reactions and, as a consequence, main advances in both topics have come from the same research groups. This chemistry was thoroughly reviewed by Mauduit and Douthwaite, from Okamoto s first report to the year 2007. 

6 Hoveyda group has arguably achieved the most important improve- 

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Allylic carbonates are better electrophdes than allylic acetates for the pallathirm-catalyzed allylic alkylation. Reaction of Eq. 5.54 shows the selective allylic alkylation of ct-nitro ester v/ith allylic carbonates v/ithont affecting allylic acetates. ... 

In the present chapter, we focus on the catalyst nature in solution using well-defined metal NPs as catal 4 ic precursors it means, soluble (or dispersible) heterogeneous pre-catalysts, as stated by Finke [6]. Some experiments described in the literature concerning the distinction between homogeneous and heterogeneous catalysts are discussed (see Section 3), followed by a particular case studied by us with regard to the catalyst nature in the allylic alkylation reaction, using preformed palladium NPs as catalytic precursors (see Section 4). 

In order to achieve a true comparison between both catalytic systems, colloidal and molecular, which display very different reaction rates, a series of experiments were carried out with the homogeneous molecular system, decreasing the catalyst concentration in the studied allylic alkylation reaction. The reaction evolution is monitored taking samples at different reaction times and analysing each of them by NMR spectroscopy (to determine the conversion) and HPLC chromatography with chiral column (to determine the enantioselectivity of I and II). For molecular catalyst systems, the Pd/substrate ratio was varied between 1/100 and 1/10,000. For the latter ratio, the initial reaction rate was found comparable to that of the colloidal system (Figure 2a), but interestingly the conversion of the substrate is quasi complete after ca. 100 h in... 

Table 1. Poison effects in activity and selectivity for the allylic alkylation reaction (Scheme 1), using [Pd/l]coii and [Pd/l]nioi as catalysts.

One of the main applications of dendrimers is in catalysis allowing easy recycling of the homogeneous catalyst by means of nanofiltration. Carbosilane dendrimers functionalized with diphenylphosphine groups at the periphery have been synthesized and characterized. Palladium complexes of these dendrimers have been used as catalysts in the allylic alkylation reaction. These dendrimeric catalysts can be used in a continuous process using a membrane reactor.509... 

They demonstrated that the C2-symmetric bis-benzothiazine (R,R)- 91 was an effective ligand in the asymmetric allylic alkylation reaction. The best result in this case was the reaction of 198 and 199 in the presence of BSA, Pd2(dba)3 and (/ ,/ )-197, which gave the product (S)-200 in 75% yield and 86% ee. More experimental data revealed that solvent effects are very important in this reaction (Scheme 57). Relatively nonpolar solvents resulted in good yields and enantiomeric excesses while reaction in CH3CN and CH2CI2 gave only racemic products in moderate yields (Table 8). 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

Van Leeuwen et al. used several generations of carbosilane dendrimers with 4, 8, 24, and 36 diphenylphosphine end-groups (Figure 4.15) for the allylic alkylation reaction of allyl trifluoracetate with sodium diethyl 2-methylmalonate.[31]... 

Other important examples of immobilized palladium catalysts (48)-(50) which were employed in Heck, Suzuki-Miyaura and allylic alkylation reactions are summarized in Fig. 4.4 [123]. Catalyst (49) is particularly noteworthy as it is a recyc-able amphiphilic resin-supported P,N-chelating Pd-complex which performs asymmetric allylic alkylations in water. 

Rhodium-Catalyzed Allylic Alkylation Reaction with Stabilized Carbon Nucleophiles... 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Bidentate palladium complexes of 5 were formed upon the addition of PdCl2, as shown by P-NMR spectroscopy, and even for the largest dendrimers steric interactions between the dendritic branches did not prevent the facile formation of the bidentate complex. Crotylpalladium chloride complexes were prepared in situ from these dendrimers and used as catalysts for allylic alkylation reactions. The regio-selectivity for the branched product for the alkylation of 3-phenylallyl acetate with diethyl sodio-2-methylmalonate increased when the higher-generation dendrimers were used, albeit at the cost of a lower activity. 

Another example of a dendritic effect observed for a core-funtionalized dendritic catalyst was described by Oosterom et al. (19) for allylic alkylation reactions (Section II). The palladium complexes of 5 catalyzed the alkylation of 3-phenylallyl acetate with sodium diethyl methylmalonate. It was observed that the reaction rate decreased and the fraction of branched product increased with increasing generation number. 

A reaction of sulfoximine 268 with ort o-substituted halobenzaldehydes 269 takes place in the presence of a catalytic amount of Pd(ii), 2,2 -bis(diphenylphosphanyl)-l,l -binaphthyl (BINAP), and caesium carbonate at 110°C to afford fully conjugated 2-phenyl-2,l-benzothiazine 2-oxides 270 with a S(vi) oxidation state (Scheme 38) <1999AGE2419>. Bis-benzothiazine 75 has been prepared from dibromo-dialdehyde 271 in a similar manner and investigated as a ligand for Pd-catalyzed allylic alkylation reactions (see Section 8.07.12.3) <20010L3321>. 

The chiral nonracemic bis-benzothiazine ligand 75 has been screened for activity in asymmetric Pd-catalyzed allylic alkylation reactions (Scheme 42) <20010L3321>. The test system chosen for this ligand was the reaction of 1,3-diphenylallyl acetate 301 with dimethyl malonate 302. A stochiometric amount of bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of KOAc were added to the reaction mixture. A catalytic amount of chiral ligand 75 along with a variety of Pd-sources afforded up to 90% yield and 82% ee s of diester 303. Since both enantiomers of the chiral ligand are available, both R- and -configurations of the alkylation product 303 can be obtained. The best results in terms of yield and stereoselectivity were obtained in nonpolar solvents, such as benzene. The allylic alkylation of racemic cyclohexenyl acetate with dimethyl malonate was performed but with lower yields (up to 53%) and only modest enantioselectivity (60% ee). 

In 2002, Trost and his co-workers reported a stereospecific ruthenium-catalyzed allylic alkylation reaction (Equation (58)). Treatment of an optically active allylic carbonate with carbon-centered nucleophiles in the presence of a ruthenium complex gives the corresponding allylic alkylated compounds with enantiomeric purity being completely maintained. Additionally, the regioselectivity is revealed not to be highly dependent on the nature of the starting carbonates. 

Catalytic enantioselective conjugate addition and allylic alkylation reactions using Grignard reagents... 

A trimethylsilyl group in compound 6 serves as a dummy substituent in order to control the regiochemistry of the allylic alkylation reaction. Oppolzer added the necessary vinylsilane structural element with a Takai reaction. 

As many endeavors in transition-metal catalysis, the design, synthesis and screening of chiral ligands have played a pivotal role in the development of the asymmetric allylic alkylation reaction. A series of C2-symmetric diphosphines such as DiPAMP, chiraphos, DIOP. and BINAP,... 

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